Bullous pemphigoid (BP) is an autoimmune bullous disease caused by autoantibodies against BP180 in the epidermal basement membrane. Autoantibody-mediated complement activation is an important process in BP pathogenesis. CD46, a crucial complement regulatory protein in the complement activation, has been reported to be involved in several autoimmune diseases. In the present study, we investigated whether CD46 plays a role in BP development. We found that sCD46 expression was significantly increased in the serum and blister fluids of BP patients and correlated with the levels of anti-BP180 NC16A antibody and C3a. Otherwise, the level of mCD46 was decreased in lesions of BP patients, whereas the complement activation was enhanced. We also found that CD46 knockdown in HaCaT human keratinocytes enhanced autoantibody-mediated complement activation. Importantly, exogenous CD46 blocked complement activation in both healthy skin sections and keratinocytes induced by exposure to pathogenic antibodies from BP patients. These data suggest that CD46 deficiency is an important factor in BP pathogenesis and that increasing CD46 levels might be an effective treatment for BP.